Long-term Efficacy and Tolerability of RPC4046 in an Open-Label Extension Trial of Patients With Eosinophilic Esophagitis.

ALIMENTARY TRACT

Long-term Efficacy and Tolerability of RPC4046 in an Open-Label Extension Trial of Patients With Eosinophilic Esophagitis

Evan S. Dellon,* Margaret H. Collins,

^‡

Marc E. Rothenberg,

^§

Yehudith Assouline-Dayan,

^jj

Larry Evans,

^¶

Sandeep Gupta,

^#

Alain Schoepfer, **

Alex Straumann,

^‡‡

Ekaterina Safroneeva,

^§§

Cristian Rodriguez,

^jjjj

Neil Minton,

^##

Steven Y. Hua,*** and Ikuo Hirano

^¶¶

*Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, Chapel Hill, North Carolina;^‡Division of Pathology and Laboratory Medicine,^§Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio;^||Department of

Gastroenterology, Carver College of Medicine, University of Iowa, Iowa City, Iowa;^¶Department of Gastroenterology, Grand Teton Research Group, Idaho Falls, Idaho;^#Department of Pediatrics, University of Illinois College of Medicine, Children’s Hospital of Illinois, Peoria, Illinois; **Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland;^‡‡Division of Gastroenterology and Hepatology, Swiss EoE Clinic, Olten, Switzerland;^§§Institute of Social and Preventative Medicine, University of Bern, Bern, Switzerland;^||||Inflammation & Fibrosis,

##Drug Safety,^***Department of Biostatistics, Celgene Corporation, Summit, New Jersey;^¶¶Division of Medicine, Gastroenterology, Feinberg School of Medicine, Chicago, Illinois

BACKGROUND & AIMS: The short-term efficacy of RPC4046, a monoclonal antibody against interleukin-13, has been shown in patients with eosinophilic esophagitis (EoE). We investigated the long-term efficacy and safety of RPC4046 in an open-label, long-term extension (LTE) study in adults with EoE.

METHODS: We analyzed data from 66 patients who completed the 16-week, double-blind, induction portion of a phase 2 study of RPC4046 (180 mg or 360 mg/wk) vs placebo and then completed a 52-week LTE, receiving open-label RPC4046 360 mg/wk. The study was conducted at 28 centers in 3 countries; patients were enrolled between September 2014 and January 2017. Outcomes were stratified by double-blind dose group and included esophageal eosinophil counts, EoE endoscopic reference score, EoE histologic scoring system score, symptom-based EoE activity index score, and safety.

RESULTS: By week 12 of the LTE, esophageal eosinophil mean and peak counts, total EoE endoscopic reference scores, and EoE histologic scoring system grade and stage scores did not differ considerably between patients who originally received placebo vs RPC4046. Most patients maintained responses through week 52. Symptom remission (symptom-based EoE activity in- dex score,£20) increased from 14% at LTE entry to 67% at LTE week 52 in placebo‒RPC4046 patients and from 30% to 54% in RPC4046‒RPC4046 (either dose) patients. Of the 28 patients who did not have a histologic response to RPC4046 during the double-blind induction phase, 10 patients (36%) achieved response during the LTE. The most common adverse events were upper respiratory tract infection (21%) and nasopharyngitis (14%).

CONCLUSIONS: One year of treatment with RPC4046 is generally well tolerated and results in continued improvement and/or maintenance of endoscopic, histologic, and clinical measures of EoE dis- ease activity relative to baseline. Trial registration: NCT02098473.

Keywords:EREFS; EoEHSS; EEsAI; Inflammation.

Abbreviations used in this paper:ADA, anti-drug antibody; AE, adverse event; DB, double-blind; DSD, daily symptom diary; EoE, eosinophilic esophagitis; EEsAI, Symptom-based Eosinophilic Esophagitis Activity In- dex; EoEHSS, Eosinophilic Esophagitis Histologic Scoring System Score;

EREFS, Eosinophilic Esophagitis Endoscopic Reference Score; hpf, high- power field; IL, interleukin; LTE, long-term extension; SAE, serious adverse event; TEAE, treatment-emergent adverse event.

Most current article

© 2021 by the AGA Institute. Published by Elsevier, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.

org/licenses/by-nc-nd/4.0/).

1542-3565

https://doi.org/10.1016/j.cgh.2020.03.036

E

osinophilic esophagitis (EoE) is a chronic, allergic/immune-mediated, clinicopathologic dis- ease of the esophagus characterized histologically by eosinophil-predominant mucosal inflammation and clini- cally by signs and symptoms of esophageal dysfunc- tion.^1,2 Complications of EoE, including strictures and food impaction, are related mostly to esophageal remod- eling and fibrostenosis and associated with a longer duration of untreated disease.^3,4 Although a topical ste- roid in orodispersible tablet form⁵ is approved for EoE treatment in Europe, there are no approved EoE treat- ments in the United States. Off-label orally/topically administered corticosteroids are a mainstay of therapy,^6–12 but their use is limited by side effects, including candidal esophagitis, oral candidiasis, and atropy of the esophageal mucosa, and long-term safety data are limited.¹³ Moreover, evidence suggests pro- longed topical corticosteroid use may be only partially effective in maintaining disease remission^14–19and asso- ciated with resistance.²⁰

Interleukin 13 (IL13), a pleotropic cytokine involved in T-helper cell 2–type inflammation, plays an important role in the pathogenesis of EoE.²¹IL13 is overexpressed in the esophageal mucosa of EoE subjects; it has been shown to induce a gene transcript profile that overlaps with the EoE-specific esophageal transcriptome²²and to modulate cellular and molecular pathways involved in eosinophil recruitment,²³ esophageal barrier function,²⁴ and tissue remodeling and fibrosis.²⁵ Simulated altered expression/blockade of IL13 in animal models produces fluctuations in EoE disease status and esophageal function.^25–28 Given the prominent role of IL13 in EoE pathogenesis, blockade of this cascade is a potential treatment target.

RPC4046 is a recombinant, humanized, highly selec- tive, monoclonal (IgG1k) antibody that recognizes the wild-type and variant human IL13 and inhibits binding to both IL13-receptor subtypes: IL13Ra1 and IL13Ra2.²⁹ The safety and efficacy of RPC4046 vs placebo were shown in the induction period of a phase 2, 16-week, randomized, controlled study in adults with symptomatic EoE (RPC02-201; ClinicalTrials.gov study ID:

NCT02098473).³⁰ Subjects completing the induction period then had the option to enroll in a subsequent 52- week, open-label, long-term extension (LTE) period;

thesefindings are reported herein.

Methods

Trial Design

We conducted an open-label LTE of the phase 2 RPC02-201 study (NCT02098473) after completion of the 16-week double-blind (DB) period in subjects with symptomatic EoE. The study was conducted at 28 cen- ters in 3 countries (Supplementary Table 1), with enrollment between September 2014 and January 2017

and study completion in October 2017. The study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice Guidelines established by the International Conference on Harmonization. Pro- tocols, amendments, and informed consent documenta- tion were reviewed and approved by the Institutional Review Boards and/or Independent Ethics Committee of each study center. All subjects provided informed consent.

Key inclusion/exclusion criteria have been reported previously³⁰ and are detailed in the Supplementary Material. During the initial DB period (16 weeks), sub- jects received placebo (n ¼34), RPC4046 180 mg (n¼ 31), or RPC4046 360 mg (n¼34) subcutaneously once weekly; 90 subjects completed the DB induction portion (through week 16). Subjects entering the LTE period were required to have 80% or greater study drug compliance and no clinically significant adverse events (AEs), as deemed by the investigator, that would pre- clude further dosing. During the LTE, all subjects received RPC4046 360 mg for 52 additional weeks; the higher dose was chosen for LTE because at the time of the study design, the dose-response and efficacy profile of RPC4046 were not known.

Prior treatment with corticosteroids for EoE was recorded at the DB baseline. Steroid-refractory status was defined as an adequate trial of systemic or topical steroids failing to result in improvements in inflamma- tion and patient symptoms, as judged by the investigator.

Outcome Measures

Primary efficacy outcome measures included esophageal eosinophil counts (mean counts [eosin- ophils per high-power field (hpf); hpf size, 0.3 mm²] calculated from the 5 most inflamed hpfs from

What You Need to Know Background

The safety and efficacy of RPC4046 was shown in the 16-week induction period of a phase 2, randomized, controlled study of adults with symptomatic eosin- ophilic esophagitis (EoE). This study reports results from the 52-week, open-label, long-term extension period.

Findings

Over 52 weeks, RPC4046 resulted in continued improvement and/or maintenance of endoscopic, histologic, and clinical measures of EoE activity, relative to baseline, and was generally well tolerated.

Implications for patient care

Encouraging findings from a study of 1 year or longer of RPC4046 treatment of patients with symptomatic EoE support confirmatory studies.

among all esophageal biopsy specimens [proximal, mid, and distal], peak counts, and peak response threshold of<15/hpf). Secondary outcome measures included daily symptom diary (DSD) scores, EoE Endoscopic Reference Score (EREFS), EoE Histologic Scoring System (EoEHSS) score, and symptom-based EoE Symptom Activity Index (EEsAI) score.^31–34 Eosinophil counts were quantified centrally by the study pathologist, who was blinded to treatment allo- cation. Endoscopic and histologic outcomes were measured at DB week 16 and at LTE weeks 12, 24, and 52 (additional information can be found in the Supplementary Methods).

Statistical Analysis: Efficacy

Efficacy analyses were conducted in the LTE analysis population, defined as all subjects receiving at least 1 dose of study drug during the LTE. Results were analyzed by the original dose group assigned to subjects during the DB induction period (placebo, RPC4046 180 mg, or RPC4046 360 mg) and presented descriptively.

The LTE baseline was defined as the last observed value scheduled, before the first dose date during the LTE.

Continuous data were summarized using mean, SD or SEM, median, minimum, and maximum values. Categoric data were summarized as the proportions of subjects.

Table 1.Patient Demographics and Disease Characteristics: LTE Population

Placebo (n¼29)

RPC4046 180 mg (n¼28)

RPC4046 360

mg (n¼29) Total (n¼86) Age,y

Mean 39.8 (11.02) 38.8 (9.79) 32.8 (9.74) 37.1 (10.56)

Minimum, maximum 21, 64 19, 59 18, 60 18, 64

Sex, n (%)

Male 19 (65.5) 18 (64.3) 19 (65.5) 56 (65.1)

Female 10 (34.5) 10 (35.7) 10 (34.5) 30 (34.9)

Race, n (%)

White 29 (100) 27 (96.4) 29 (100) 85 (98.8)

Black or African American 0 1 (3.6) 0 1 (1.2)

Years since EoE diagnosis

Mean 4.331 (3.003) 4.220 (3.900) 3.711 (2.864) 4.086 (3.253)

Minimum, maximum 0.14, 10.89 0.12, 15.52 0.04, 9.53 0.04, 15.52

Steroid stratification factor, n (%)

Steroid-refractory 14 (48.3) 12 (42.9) 15 (51.7) 41 (47.7)

Not steroid-refractory 15 (51.7) 16 (57.1) 14 (48.3) 45 (52.3)

Baseline eosinophil count/hpf

Mean (SD) 96.93 (54.45) 119.60 (80.80) 125.61 (74.53) 113.98 (70.96)

Minimum, maximum 23.6, 189.8 21.4, 273.0 22.2, 369.2 21.4, 369.2

Baseline peak eosinophil count/hpf

Mean (SD) 111.0 (60.72) 135.4 (88.18) 143.0 (83.67) 129.8 (78.62)

Minimum, maximum 31, 212 24, 304 26, 389 24, 389

LTE baseline eosinophil count/hpf^a

Mean (SD) 88.39 (55.87) 27.12 (36.86) 25.61 (30.51) 47.27 (51.35)

Minimum, maximum 12.0, 265.4 0.0, 133.6 0.0, 123.4 0.0, 265.4

LTE baseline peak eosinophil count/hpf^a

Mean (SD) 102.6 (63.05) 31.2 (41.55) 31.3 (38.35) 55.3 (59.11)

Minimum, maximum 16, 302 0, 159 0, 157 0, 302

LTE baseline EREFS total score

Mean (SD) 8.1 (5.14) 5.5 (3.83) 6.5 (4.43) 6.7 (4.59)

Minimum, maximum 0, 18 0, 14 0, 18 0, 18

LTE baseline EoEHSS grade score

Mean (SD) 40.9 (13.55) 21.5 (12.41) 20.0 (6.47) 27.5 (14.67)

Minimum, maximum 16.27, 63.49 4.76, 66.87 10.32, 33.33 4.76, 66.87

LTE baseline EoEHSS stage score

Mean (SD) 40.9 (12.69) 21.7 (12.64) 19.4 (6.98) 27.4 (14.66)

Minimum, maximum 17.46, 58.73 1.59, 59.33 9.33, 34.92 1.59, 59.33

LTE baseline EEsAI mean score

Mean (SD) 40.3 (23.36) 37.8 (22.69) 30.1 (25.12) 36.0 (23.88)

Minimum, maximum 0, 78 0, 76 0, 76 0, 78

LTE baseline DSD composite score

Mean (SD) 21.0 (18.55) 20.0 (17.63) 13.8 (16.77) 18.2 (17.66)

Minimum, maximum 0.0, 51.7 0.0, 46.7 0.0, 45.5 0.0, 51.7

DSD, daily symptom diary; EEsAI, Eosinophilic Esophagitis Activity Index; EoE, eosinophilic esophagitis; EoEHSS, Eosinophilic Esophagitis Histologic Scoring System Score; EREFS, Eosinophilic Esophagitis Endoscopic Reference Score; LTE, long-term extension.

aBaseline was defined as the last observed score before thefirst dose of study drug during the LTE.

Safety Analyses

No statistical hypothesis testing was performed on safety results. AEs were described as the raw number of treatment-emergent AEs (TEAEs), percentages of sub- jects, and as exposure-adjusted incidence rates per 100 patient-years of exposure. TEAEs were defined as AEs with onset on or after thefirst dose of study drug during the LTE, or AEs that started before thefirst dose of study drug during the LTE but worsened on or after thefirst dose of study drug during the LTE. Serious AEs (SAEs) also were assessed.

Results

Disposition

Among the 90 subjects who completed the DB treatment period, 86 were enrolled in the LTE (placebo,

n¼29; RPC4046 180 mg, n¼28; and RPC4046 360 mg, n ¼ 29) (Supplementary Figure 1). Twenty of the 86 subjects (23%) did not complete the full 52-week dura- tion as part of the LTE. Five of these patients had higher mean esophageal eosinophil counts before study drug discontinuation relative to baseline LTE; however, study discontinuations were not associated with the long-term efficacy of RPC4046. Reasons for study drug discontin- uation during the LTE included withdrawal of consent (n¼7), AE (n¼6), noncompliance (n¼3), other (n¼ 2), investigator decision (n¼1), and pregnancy (n¼1).

Demographic and Disease Characteristics

Demographic and disease characteristics of subjects entering the LTE were consistent with the population characteristics of the initial DB induction phase of the trial. Subjects enrolled in the LTE had a mean age of 37.1 years, with a mean of 4.1 years since their EoE

Figure 1.Clinical efficacy outcomes. Clinical results for the long-term extension (LTE) patient group at main study baseline, LTE study entry, week 12, week 24, and week 52. (A) The mean esophageal eosinophil count per high-power field. (B) The proportion of subjects achieving a peak esophageal eosinophil count less than 15 eosinophils per high-powerfield. (C) The mean total eosinophilic esophagitis endoscopic reference score (EREFS) (endoscopic findings analyzed according to the modified scoring system described by Hirano et al³¹). (D) The proportion of subjects achieving symptomatic remission as determined by an Eosinophilic Esophagitis Activity Index (EEsAI) score of 20 or less (LTE population). OLE, open-label extension.

diagnosis; approximately 48% were steroid-refractory (Table 1).

Clinical Efficacy

At LTE entry, the mean esophageal eosinophil counts for subjects previously treated with placebo were sub- stantially higher than for subjects previously receiving active treatment (Table 1;Figure 1A); by LTE week 12, counts had decreased to the levels observed in both RPC4046 groups, which was maintained through LTE week 52 (Figure 1A). Similarly, at LTE entry, peak esophageal eosinophil counts in subjects previously treated with placebo were 3-fold greater than in subjects previously receiving active treatment (Table 1); these counts had decreased to levels observed in both RPC4046 groups by LTE week 12, which was maintained through LTE week 52 (Figure 2A). No effect of RPC4046 on the mean absolute blood eosinophil levels was observed at LTE week 52 (Supplementary Table 2). The proportion of responders (peak esophageal eosinophil count, <15 hpf) increased from LTE week 12 to LTE week 52 in all 3 groups (placebo, 28.6% [week 12] to 57.1% [week 52]; RPC4046 180 mg, 53.6% to 73.9%;

RPC4046 360 mg, 44.4% to 59.1%) (Figure 1B).

The EREFS total and composite (inflammation and remodeling) scores over all locations decreased from LTE baseline through LTE week 52 in subjects previously randomized to placebo; in those previously receiving active treatment during the DB induction phase, further improvement beyond the LTE baseline was seen at both week 12 and week 52 (Figures 1C and 3A–C). At LTE week 52, decreases in EREFS scores were numerically greater in subjects previously treated with placebo vs RPC4046 (mean change from LTE baseline to week 52 for placebo, -5.0; for RPC4046 180 mg, -1.3; and for RPC4046 360 mg, -2.9). EREFS individual components scores over all locations (Supplementary Table 3) and EREFS components by location (data not shown) were similar across groups throughout the LTE period. EREFS total scores over time in individual subjects are shown in Supplementary Figure 2.

EoEHSS grade scores for subjects previously treated with placebo were 2-fold greater than for subjects pre- viously treated with RPC4046 (either dose) at LTE entry (Table 1). By LTE week 52, EoEHSS grade scores had decreased substantially for subjects previously treated with placebo (mean change from LTE baseline to week 52 for placebo, -21.5; for RPC4046 180 mg, -2.9; and for RPC4046 360 mg, 2.1) (Figure 3D). The mean absolute EoEHSS grade scores were similar across the treatment Figure 2.Peak eosinophils (EOS) over time (baseline double-blind week 16, long-term extension [LTE] weeks 12, 24, and 52) by treatment group. (A) Average of individuals within each treatment group: placebo, RPC4046 180 mg, and RPC4046 360 mg.

(B) Individual data from the placebo group. (C) Individual data from the RPC4046 180 mg group. (D) Individual data from the RPC4046 360 mg group (LTE population). OLE, open-label extension.

groups at LTE week 52 (19.9, 19.5, and 21.9, respec- tively). At LTE entry, the EoEHSS stage scores for sub- jects previously treated with placebo were 2-fold greater than for subjects previously receiving active treatment.

By LTE week 52, scores for subjects previously treated with placebo had decreased (mean change from LTE baseline to week 52 for placebo, -20.8; for RPC4046 180 mg, -1.9; and for RPC4046 360 mg, 3.5) (Figure 3E), and the mean absolute values generally were similar to those in both RPC4046 groups (20.4, 21.4, and 22.2, respectively).

The EEsAI mean (SD) scores for the placebo, RPC4046 180 mg, and RPC4046 360 mg groups improved from LTE baseline through LTE week 12 (mean change: placebo, -9.1; RPC4046 180 mg, -9.1; and RPC4046 360 mg, -8.7) and from LTE baseline through LTE week 52 (mean change: placebo, -21.1; RPC4046 180 mg, -10.6; and RPC4046 360 mg, -14.6). The pro- portion of subjects achieving symptomatic remission (EEsAI score,20) showed a similar trend of increase in all treatment groups from LTE baseline through LTE week 52 (Figure 1D). The proportion of subjects achieving EEsAI remission increased in the placebo (13.8% [LTE baseline] to 66.7% [LTE week 52]), RPC4046 180 mg (25.0% to 41.7%), and RPC4046 360 mg (34.5% to 68.2%) groups (Supplementary Table 4).

EEsAI scores over time in individual subjects are shown inSupplementary Figure 3. At LTE entry, the mean DSD composite score in subjects previously treated with RPC4046 360 mg were lower than in subjects previously treated with placebo or RPC4046 180 mg. By LTE week

52, scores for all groups had decreased (mean change:

placebo, -8.61; RPC4046 180 mg, -11.31; and RPC4046 360 mg, -8.46) (Supplementary Table 5).

Further post hoc analysis assessed whether peak esophageal eosinophil count response achieved with randomized treatment by week 16 of the DB induction period was maintained at week 52 with RPC4046 360- mg treatment (Table 2). A majority of the subjects (69.0%) who had a histologic response at DB week 16 with active treatment (RPC4046 180 mg or 360 mg) maintained it at LTE week 52 (20 of 29); 10.3% (3 of 29) lost prior response. Among subjects entering LTE who were not histologic responders (peak eosinophil counts, 15 hpf) after 16 weeks of active study drug treatment during the DB induction phase (n ¼28), 10 (35.7%) subjects (RPC4046 180 mg, n ¼7; RPC4046 360 mg, n ¼ 3) were able to achieve histologic response with RPC4046 360 mg at LTE week 52 (Table 2;Figure 2Cand D).

Steroid-Refractory Vs Non–Steroid-Refractory Subjects

Forty-one of 86 subjects enrolled in the LTE study were considered steroid-refractory. No notable differ- ences were observed between the steroid-refractory and non–steroid-refractory groups for mean changes from LTE entry over the LTE period in mean esophageal eosinophil counts (Supplementary Figure 4AandB), DSD composite scores and components (Supplementary Figure 4C and D), EREFS total score (Supplementary

=

Figure 3.Mean (SEM) changes from long-term extension (LTE) baseline to LTE weeks 12, 24, and 52 for Eosinophilic Esophagitis Endoscopic Reference Score (EREFS) (total, inflammation, and remodeling), and Eosinophilic Esophagitis His- tologic Scoring System Score (EoEHSS) grade and stage scores. (A) EREFS total score. (B) EREFS inflammation composite score. (C) EREFS remodeling composite score. (D) EoEHSS grade score. (E) EoEHSS stage score (LTE population).

Table 2.Peak EOS Count Responder Analysis: Observed Cases in the LTE Population

Randomized treatment assignment at DB baseline

RPC4046 total (N¼57) Placebo

(N¼29)

RPC4046 180 mg (n¼28)

RPC4046 360 mg (n¼29) Proportion of patients with response at DB week 16, n/N (%)

Peak EOS<15 at DB week 16 0/29 (0) 14/28 (50.0) 15/29 (51.7) 29/57 (50.9)

Peak EOS15 at DB week 16 29/29 (100) 14/28 (50.0) 14/29 (49.3) 28/57 (49.1)

Proportion of patients with response at DB week 16 and LTE week 52, n/N (%) Peak EOS<15 at DB week 16 and peak EOS<15 at

LTE seek 52^a

0/0 (0) 10/14 (71.4) 10/15 (66.7) 20/29 (69.0)

Peak EOS<15 at DB week 16 and peak EOS15 at LTE week 52^a

0/0 (0) 1/14 (7.1) 2/15 (13.3) 3/29 (10.3)

Peak EOS15 at DB week 16 and peak EOS<15 at LTE week 52^b

12/29 (41.4) 7/14 (50.0) 3/14 (21.4) 10/28 (35.7)

Peak EOS15 at DB week 16 and peak EOS15 at LTE week 52^b

9/29 (31.0) 5/14 (35.7) 7/14 (50.0) 12/28 (42.9)

DB, double blind; EOS, eosinophilic esophagitis; LTE, long-term extension.

aDenominator is the number of subjects with a peak EOS less than 15 at DB week 16.

bDenominator is the number of subjects with a peak EOS of 15 or higher at DB week 16.

Table 3), or EEsAI scores (seeSupplementary Materials Results: Steroid-Refractory and Non-Steroid Refractory Subjects for detailed results).

Atopic Subjects

Sixty-one of 90 (67.8 %) subjects who completed the DB induction period had a history of atopy/allergies at baseline, of whom 45 received active study drug. Forty- three of 60 atopic subjects from the DB period completed 52 weeks of LTE treatment. Overall, no marked differences in histologic response (Supplementary Table 6), endoscopic (EREFS;

Supplementary Table 7), or symptom scores (EEsAI remission score, 20) (Supplementary Table 4) were observed in atopic subjects vs the overall study popula- tion after long-term treatment with RPC4046 360 mg. No significant impact on IgE levels was observed in atopic patients or the overall study population.

Safety Assessments

Generally, RPC4046 was well tolerated; the majority of AEs reported in the LTE period were consistent with those in the induction period, with no new clinically

significant AEs identified with longer-term treatment.

Overall, the majority of subjects with TEAEs had TEAEs of mild or moderate severity (83.1%). Seventy-one sub- jects (82.6%) reported 1 or more TEAEs; 6 subjects (7%) reported 1 or more SAEs (Table 3; Supplementary Table 8). All SAEs with the exception of the case of schizophrenia were resolved by the end of the study. The most commonly reported TEAEs (10%) were an upper respiratory tract infection in 18 subjects, nasopharyngitis in 12 subjects, sinusitis and oropharyngeal pain in 10 subjects each, and headache in 9 subjects (Table 3). In- jection site reaction was reported in 18.6% of subjects in the LTE period, with injection-site erythema and hema- toma occurring in 4 subjects (4.7%) (5.5 exposure- adjusted incidence rate/100 patient-years of exposure) each (Supplementary Table 9). Of note, there were no significant changes in blood eosinophils from baseline to week 52 in the LTE population (Supplementary Table 2).

Increased blood eosinophil levels (1000 cells/mL) were observed in 11 subjects during LTE, including baseline, that were mostly transitory or observed at single time points; none were greater than 2100 cells/mL. No TEAEs were attributed to increases in blood eosinophil counts.

The incidence of immunogenicity was low; only 4 subjects tested positive for antidrug antibody (ADA) across the DB and LTE periods. Two subjects, both in the Table 3.Summary of Safety Findings by Study Group During the LTE Period: LTE Population

Randomized treatment assignment at DB baseline

Total (n¼86) Placebo

(n¼29)

RPC4046 180 mg (n¼28)

RPC4046 360 mg (n¼29)

Subject with1 TEAE, n (%) 21 (72.4) 26 (92.9) 24 (82.8) 71 (82.6)

Subject with1 possible, probable, or related TEAE,^an (%) 8 (27.6) 13 (46.4) 14 (48.3) 35 (40.7) Subject with TEAE by maximum severity,^bn (%)

Mild 12 (41.4) 11 (39.3) 10 (34.5) 33 (38.4)

Moderate 6 (20.7) 11 (39.3) 9 (31.0) 26 (30.2)

Severe 3 (10.3) 4 (14.3) 5 (17.2) 12 (14.0)

Subject with1 serious TEAE,^cn (%) 0 2 (7.1) 4 (13.8) 6 (7.0)

Subject with TEAE leading to study drug discontinuation,^dn (%) 3 (10.3) 1 (3.6) 2 (6.9) 6 (7.0)

Subject with TEAE leading to withdrawal from study,^dn (%) 0 0 1 (3.4) 1 (1.2)

Most frequent TEAE (10% of subjects), n (%) [EAIR/100 PYE]

Upper respiratory tract infection 9 (31.0) [38.8] 6 (21.4) [23.3] 3 (10.3) [12.5] 18 (20.9) [24.7]

Nasopharyngitis 1 (3.4) [4.3] 3 (10.7) [11.6] 8 (27.6) [33.3] 12 (14.0) [16.4]

Oropharyngeal pain 1 (3.4) [4.3] 7 (25.0) [27.2] 2 (6.9) [8.3] 10 (11.6) [13.7]

Sinusitis 2 (6.9) [8.6] 2 (7.1) [7.8] 6 (20.7) [24.9] 10 (11.6) [13.7]

Headache 3 (10.3) [12.9] 4 (14.3) [15.5] 2 (6.9) [8.3] 9 (10.5) [12.3]

Injection site reactions, n (%) [EAIR/100 PYE]

Any injection site reaction 3 (10.3) 6 (21.4) 7 (24.1) 16 (18.6)

Injection site erythema 1 (3.4) [4.3] 1 (3.6) [3.9] 2 (6.9) [8.3] 4 (4.7) [5.5]

Injection site hematoma 1 (3.4) [4.3] 1 (3.6) [3.9] 2 (6.9) [8.3] 4 (4.7) [5.5]

DB, double-blind; EAIR, exposure-adjusted incidence rate; LTE, long-term extension; PYE, patient-years of exposure; TEAE, treatment-emergent adverse event.

aSubjects reporting more than 1 TEAE were counted only once using the closest relationship to study drug.

bSubjects reporting more than 1 TEAE were counted only once using the highest severity.

cSerious adverse events included unlikely or not related to study drug (acute asthma exacerbation, schizophrenia, diverticulitis with microperforation, right femur fracture [motorcycle accident]) and possibly related (acute cholecystitis, spontaneous abortion).

dBecause of how data were captured on the disposition electronic case report form, only 1 subject was reported to have TEAEs leading to withdrawal from the study. However, the 6 subjects who discontinued study drug because of TEAEs also withdrew from the study.

RPC4046 180 mg group, tested positive for ADA during the DB period, 1 of whom was only ADA (þ) at DB day 1 (predose) and DB week 12; the other subject was ADA (þ) at DB weeks 12 and 16 and LTE weeks 2, 4, and 12, but ADA (-) at subsequent LTE visits. Two additional subjects in the DB randomized placebo group were ADA (þ) during LTE, 1 at LTE week 24 only and the other at LTE weeks 12, 24, and 52 (additional details are pro- vided in the Supplementary Materials Immunogenicity Assessment). The potential impact of immunogenicity on RPC4046 cannot be characterized because only a few subjects had ADAs during the trial period.

Discussion

Targeted EoE immunotherapies present a potential treatment option for the significant numbers of patients who are refractory to current therapies.³⁵Several biologic monoclonal antibodies have been evaluated,³⁶ but long- term data are limited.³⁷ In the DB randomized, placebo- controlled portion of this phase 2 trial, the novel anti- IL13 monoclonal antibody RPC4046 showed efficacy as a targeted therapeutic option in EoE patients.³⁰We report several notablefindings in the open-label LTE portion of this trial. Overall, subjects initially treated with RPC4046 (180 mg and 360 mg) in the DB phase had continued endoscopic, histologic, and clinical improvement of EoE disease activity for an additional 52 weeks. Improvements were shown by continued reductions in the mean and peak esophageal eosinophil count, stable histologic scores as determined by EoEHSS, and continued improvement in mucosal appearance by EREFS. Moreover, subjects who initially received placebo experienced improvements as early as the LTE week 12 visit, despite not having received an intravenous RPC4046 loading dose; these improve- ments were maintained for the remaining LTE period.

Subjects who received RPC4046 180 mg during the DB period did not show significant differences in improve- ment when given an increased dose of 360 mg RPC4046 during LTE, indicating a consistent long-term effect of RPC4046. Importantly, similar responses were seen in the non–steroid-refractory subgroup and the difficult-to-treat steroid-refractory subgroup (a group with no current pharmacologic options who would be well-suited to bio- logic therapy). Although not all patients reached pre- defined peak esophageal eosinophil values defining treatment response, most patients showed notable de- creases in peak eosinophil counts throughout the long- term treatment period relative to baseline.

RPC4046 was well tolerated with little immunoge- nicity elicited in the LTE period. Overall, the majority of TEAEs were mild or moderate in severity. No deaths occurred during the LTE, and only 2 SAEs were assessed as possibly related to the study drug (cholecystitis and spontaneous abortion), which resolved by study end.

The current open-label LTE portion of this phase 2 study includes long prospective LTE follow-up studies in

EOE patients, providing long-term data on biologic treatment in EoE using validated outcome measures. A potential limitation is that approximately 25% (20 of 86) of subjects were not able to complete the full 52-week LTE duration. The LTE portion of the study was open- label in design and thus not blinded, which limited the ability to conduct statistical comparisons. Symptom data, in particular, should be interpreted with caution because patients knew they were receiving an active medication;

however, changes in symptom data were similar in the DB and LTE periods. Evaluation of only RPC4046 360 mg in the LTE period is another potential limitation; how- ever, the safety and immunogenicity data suggest that this dose was well tolerated, with no new safety signals identified with longer-term treatment. Finally, the cur- rent study was not stratified by EoE endotype; therefore, evaluation of RPC4046 in patients with distinct EoE endotypes³⁸ remains an area for further exploration.

The current study showed no significant safety con- cerns in subjects receiving RPC4046 for 52 weeks and beyond. Subjects in the LTE period had clinical, endo- scopic, and histologic improvement of EoE relative to baseline; those who switched from placebo to RPC4046 showed clinical disease improvement as early as 12 weeks. Subgroup analyses further suggest efficacy in both the steroid-refractory and non–steroid-refractory populations. These data support further confirmatory studies of RPC4046.

Supplementary Material

Note: To access the supplementary material accom- panying this article, visit the online version of Clinical Gastroenterology and Hepatologyatwww.cghjournal.org, and athttps://doi.org/10.1016/j.cgh.2020.03.036.

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Reprint requests

Address requests for reprints to: Evan S. Dellon, MD, MPH, Division of Gastroenterology and Hepatology, University of North Carolina–Chapel Hill, School of Medicine, 130 Mason Farm Road, 4140 Bioinformatics Building, Campus Box 7080, Chapel Hill, North Carolina 27599-7080. e-mail:

evan_dellon@med.unc.edu; fax: (919) 843-2508.

Acknowledgments

The authors thank Keith Usiskin for his critical review of the manuscript.

Samorn Biosciences and Peloton Advantage, LLC, an OPEN Health company, provided editorial support in the development of this manuscript, funded by Celgene Corporation. The data that support thefindings of this study are not available in an online or public repository. However, data are available from the

authors upon reasonable request and with the permission of Celgene Corpo- ration. Celgene is committed to responsible and transparent sharing of clinical trial data with patients, health care practitioners, and independent researchers for the purpose of improving scientific and medical knowledge, as well as fostering innovative treatment approaches. For more information, please visit: https://www.celgene.com/research-development/clinical-trials/clinical- trials-data-sharing.

A complete list of investigators in the phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group open-label, extension study evaluating the clinical efficacy and safety of RPC4046 in adult subjects with eosinophilic esophagitis (A Phase 2, Multi-Center, Multi-national, Randomized, Double-blind, Placebo-controlled Parallel-group Clinical Trial to Evaluate the Efficacy and Safety of RPC4046 in Adult Subjects With Eosinophilic Esopha- gitis LTE) is provided in theSupplementary Appendix.

CRediT Authorship Contributions

Evan S. Dellon, MD, MPH (Conceptualization: Equal; Data curation: Equal;

Writing–original draft: Equal; Writing–review & editing: Equal; data inter- pretation: Equal)

Margaret Collins, MD (Conceptualization: Equal; Data curation: Equal;

Writing–original draft: Equal; Writing–review & editing: Equal; data inter- pretation: Equal)

Marc E. Rothenburg, MD; PhD (Conceptualization: Equal; Data curation:

Equal; Writing–original draft: Equal; Writing–review & editing: Equal; data interpretation: Equal)

Yehudith Assouline Dayan, MD (Conceptualization: Equal; Data curation:

Equal; Writing–original draft: Equal; Writing–review & editing: Equal; data interpretation: Equal)

Larry Evans, DO (Conceptualization: Equal; Data curation: Equal; Writing– original draft: Equal; Writing–review & editing: Equal; data interpretation: Equal)

Sandeep Gupta, PhD (Conceptualization: Equal; Data curation: Equal;

Writing–original draft: Equal; Writing–review & editing: Equal; data inter- pretation: Equal)

Alain Schoepfer, PDþMER1 (Conceptualization: Equal; Data curation:

Equal; Writing–original draft: Equal; Writing–review & editing: Equal; data interpretation: Equal)

Alex Straumann, MD (Conceptualization: Equal; Data curation: Equal; Writing– original draft: Equal; Writing–review & editing: Equal; data interpretation: Equal)

Ekaterina Safroneeva, PhD (Conceptualization: Equal; Data curation: Equal;

Writing–original draft: Equal; Writing–review & editing: Equal; data inter- pretation: Equal)

Cristian Rodriguez, MD (Formal analysis: Equal; Writing–review & editing:

Equal; data interpretation: Equal)

Neil Minton, MD (Formal analysis: Equal; Writing–review & editing: Equal;

data interpretation: Equal)

Steven Y. Hua, PhD (Formal analysis: Equal; Writing–review & editing:

Equal; data interpretation: Equal)

Ikuo Hirano, MD (Conceptualization: Equal; Data curation: Equal; Writing– original draft: Equal; Writing– review & editing: Equal; data interpretation:

Equal).

Conflicts of interest

These authors disclose the following: Evan S. Dellon has served as a consul- tant for Adare, Aimmune, Alivio, Allakos, AstraZeneca, Banner, Biorasi, Calypso, Celgene Corporation, Enumeral, Esocap, Gossamer Bio, GSK, Regeneron, Robarts, Salix, and Shire, has received grant/research support from Adare, Allkos, Celgene Corporation, GSK, Meritage, Miraca, Nutricia, Regeneron, and Shire, and has received educational grants from Allakos, Banner, and Holoclara; Ikuo Hirano has served as a consultant for Adare, Allakos, Celgene Corporation, Esocap, Gossamer Bio, Regeneron, and Shire, and has received grant/research support from Adare, Allakos, Celgene Corporation, Regeneron, and Shire; Margaret H. Collins has served as a consultant for Allakos, Celgene Corporation, Esocap, Regeneron, and Shire, and has received grant/research support from Celgene Corporation, Regen- eron, and Shire; Marc E. Rothenberg has served as a consultant for Pulm One, Spoon Guru, ClostraBio, Celgene, and AstraZeneca, has an equity interest in Pulm One, Spoon Guru, and ClostraBio, has received royalties from Teva Pharmaceuticals (reslizumab), Mapi Research Trust (PEESSv2), and UpToDate;

and is an inventor of patents owned by Cincinnati Children’s; Hospital Sandeep Gupta has received grant/research support from Shire and served as a consultant for Abbott, Adare, Allakos, Gossamer, Celgene Corporation, and QOL; Alain M. Schoepfer has received grant/research support from Adare, Celgene Corporation, Falk, Merck Sharp & Dohme, and Regeneron, and has served as a consultant and advisor for AbbVie, Adare, Celgene Corporation, Falk, Merck Sharp & Dohme, and Regeneron; Alex Straumann has served as a consultant for Actelion, Calypso, Celgene Corporation, Falk, GlaxoSmithKline, Merck, Merck Sharp & Dohme, Novartis, Nutricia, Pfizer, Regeneron-Sanofi, Roche-Genentech, and Tillotts, and has received grant/research support from Celgene Corporation; Ekaterina Safroneeva has served as a consultant for Aptalis Pharma, Celgene Corporation, Novartis, and Regeneron; and Cristian Rodriguez, Neil Minton, and Steven Y. Hua are employees and shareholders of Celgene Corporation. The remaining authors disclose no conflicts.

Funding

This study was sponsored by Celgene Corporation.

Supplementary Appendix

Study Investigators

The study investigators at the initiated sites were as follows: Canada: Fergal Donnellan, Gastrointestinal Research Unit, The Gordon and Leslie Diamond Centre, Vancouver Hospital; Marietta Iacucci, Gastrointestinal Research Group, University of Calgary Health; and Wil- liam Paterson, Hotel Dieu Hospital; Switzerland: Alain Schoepfer, Centre Hospitalier Universitaire Vaudois, and Alex Straumann, Swiss EoE Clinic; United States: Pablo Abonia, Cincinnati Children’s Hospital Medical Center;

Yehudith Assouline-Dayan, University of Iowa Hospitals and Clinics; Kamran Ayub, Southwest Gastroenterology;

Allan Coates, West Michigan Clinical Research Center, Gastroenterology Associates of Western Michigan; Sid- ney Cohen, Thomas Jefferson University; Evan Dellon, University of North Carolina; Taddese Desta, Precision Research Institute, LLC; Larry Evans, Grand Teton Research Group; Gary Falk, The University of Pennsyl- vania; Steven Fein, Digestive Health Center; Nielsen Fernandez-Becker, Stanford University; David Fleischer, Children’s Hospital Colorado; Keith Friedenberg, Great Lakes Gastroenterology Research; Fayez Ghishan, The University of Arizona Clinical and Translational Science;

Sarah Glover, University of Florida; Gary Goldstein, Vi- sions Clinical Research; Vikram Gopal, Borland-Groover Clinic; Craig Gross, Desert Sun Clinical Research, LLC;

Robert Hardi, Metropolitan Gastroenterology Group Chevy Chase Clinical Research; Ikuo Hirano, North- western University; Subra Kugathasan, Emory Univer- sity; Brian Lacy, Dartmouth-Hitchcock Medical Center;

Jeffery Lewis, Children’s Center for Digestive Healthcare;

Paul Menard-Katcher, University of Colorado Anschutz Medical Center; Benjamin Mitlyng, Minnesota Gastroen- terology; Fouad Moawad, Walter Reed Army Medical Center; Rodney Perez, Asheville Gastroenterology Asso- ciates; Kathryn Peterson, University of Utah; Francisco Ramirez, Clinical Studies Unit, Mayo Clinic Arizona;

Vonda Reeves-Darby, Gastrointestinal Associates; Ron Schey, Temple University Hospital; Javaid Shad, Alliance Clinical Research; Michael Vaezi, Vanderbilt University Medical Center; John Wo, Indiana University; and Salam Zakko, Connecticut Clinical Research Foundation.

Note that the 40 listed sites were initiated for participation in this study; of these sites, 30 enrolled at least 1 subject.

Study Administration

The study administration was as follows: the mem- bers of the Phase 2, Multi-Center, Multi-national, Randomized, Double-blind, Placebo-controlled Parallel- group Clinical Trial to Evaluate the Efficacy and Safety of RPC4046 in Adult Subjects With Eosinophilic Esophagitis protocol committee designed the trial in collaboration

with Celgene. Study data were collected by a contract research organization (Agility Clinical, Inc, Carlsbad, CA) and analyzed by Celgene. Celgene and the Phase 2, Multi-Center, Multi-national, Randomized, Double-blind, Placebo-controlled Parallel-group Clinical Trial to Eval- uate the Efficacy and Safety of RPC4046 in Adult Subjects With Eosinophilic Esophagitis study group interpreted the data jointly and safety data were reviewed by a safety review. All authors had full access to the data. The first author wrote thefirst draft of the manuscript, and all authors contributed to subsequent drafts, made a collective decision to submit the manuscript for publi- cation, and vouch for the completeness and veracity of the data and analyses and for the adherence to the protocol, available at NEJM.org. Editorial support was provided by Celgene. Confidentiality agreements were in place between Celgene and all authors.

The Protocol Committee included the following: Evan S. Dellon, MD, MPH (University of North Carolina School of Medicine, Chapel Hill, NC); Ikuo Hirano, MD (Division of Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, IL); Alex Straumann, MD (Swiss EoE Clinic, Olten, Switzerland); and Alain M.

Schoepfer, MD (Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland).

The Safety Review Committee included the following:

Sandeep Gupta, MD (Pediatrics and Internal Medicine, University of Illinois College of Medicine, Peoria, IL); and Paul Frohna, MD, PhD, PharmD, and Michael Grimm, MD (formerly with Receptos, a wholly owned subsidiary of Celgene, Inc, San Diego, CA).

Inclusion Criteria

As part of the initial phase 2 study, subjects were required to be 18 to 65 years of age with a confirmed diagnosis of EoE. Subjects were required to have symp- toms of dysphagia for a minimum of 4 days over 2 weeks (within the 4-week screening period) and histologic ev- idence of EoE, defined as a peak count of 15 or more eosinophils per hpf (microscope hpf, 0.3 mm²) at any 2 of 3 levels of the esophagus (proximal, mid, distal) when off anti-inflammatory therapy for EoE. Subjects must have previously received an adequate trial of a proton pump inhibitor and been confirmed to not have proton pump inhibitor–responsive EoE. Subjects with a partial response to a proton pump inhibitor who met all other eligibility criteria could be enrolled; prospective subjects who discontinued use of a proton pump inhibitor had to wait at least 4 weeks before their screening endoscopy; if a prospective subject was receiving a proton pump in- hibitor at screening, they must have been receiving a stable dose for at least 4 weeks before the screening endoscopy and agreed to continue on a the same dose through week 16; males and females of childbearing potential had to agree to use adequate birth control measures during the trial and for 5 months after their

last dose of study drug; and all females of childbearing potential must have had a negative serum pregnancy test at screening and a negative urine (or serum) pregnancy test before dosing on day 1.

Patients who completed the double-blind treatment period of the phase 2 study, who showed 80% or better study drug compliance, and who had no clinically sig- nificant adverse events during initial therapy the were eligible to be enrolled in the LTE period.

Exclusion Criteria

Exclusion criteria included clinical or endoscopic evi- dence of the presence of any other disease that may have interfered with or affected the histologic, endoscopic, and clinical symptom end points for this trial (eg, erosive esophagitis grade 2 or higher, Barrett’s esophagus, upper gastrointestinal bleed, eosinophilic gastritis or gastroen- teritis, active Helicobacter pylori infection, duodenal or gastric eosinophilia on screening endoscopy, inflamma- tory bowel disease, significant hiatal hernia [>3 cm]);

presence of esophageal varices; evidence of severe endoscopic structural abnormality in the esophagus (eg, high-grade stenosis in which an 8- to 10-mm endoscope could not pass through the stricture without dilation at the time of endoscopy); primary causes of esophageal eosinophilia other than EoE; evidence of immunosup- pression or were receiving systemic immunosuppressive or immunomodulating drugs (eg, methotrexate, cyclo- sporine, interferona, tumor necrosis factorainhibitors, antibodies to IgE, and so forth) within 5 drug half-lives before screening; were receiving systemic or swallowed topical corticosteroid medication; prospective subjects with EoE treated with a corticosteroid must not have received a systemic corticosteroid within 8 weeks or swallowed topical corticosteroids within 4 weeks of the screening endoscopy or the start of the daily clinical symptom diary data collection during screening, which- ever was performed first; presence of any other disease making conduct of the protocol or interpretation of the trial results difficult or that would have put the prospec- tive subject at risk by participating in the trial (eg, infec- tion causing eosinophilia, gastritis, colitis, irritable bowel syndrome, and celiac disease, which have similar symp- toms, neurologic or psychiatric illness that compromised the prospective subject’s ability to accurately document symptoms of EoE, and so forth); liver function impairment or persisting increases of aspartate aminotransferase or alanine aminotransferase greater than 2 times the upper limit of normal, or direct bilirubin level greater than 1.5 times the upper limit of normal; systemic or diarrheal illness after travel or residence in endemic areas of parasitic/helminthic infections, history of clinical schis- tosomiasis, history of travel to endemic areas within the preceding 6 months; ongoing infection (eg., hepatitis B or C, human immunodeficiency virus, active tuberculosis);

pregnancy or lactation; concurrent treatment with

another investigational drug; prospective subjects could not have participated in a concurrent investigational drug trial or have received an investigational drug within 5 drug half-lives before signing the informed consent form for this trial; weight of less than 40 kg (88.2 pounds) or more than 125 kg (275 pounds); history of idiopathic anaphylaxis or a known history of a major immunologic reaction (such as anaphylactic reaction, anaphylactoid reaction, or serum sickness) to an IgG-containing agent;

history of cancer or lymphoproliferative disease, other than a successfully treated nonmetastatic cutaneous squamous cell or basal cell carcinoma or adequately treated cervical carcinoma in situ, within 10 years of screening; or esophageal dilation for symptom relief during the screening period and within 4 weeks before the baseline assessment of dysphagia or anticipated to be performed during the trial.

Protocol Amendments

The original protocol (dated March 13, 2014) was amended 3 times. The first amendment (dated May 16, 2014) was implemented before enrollment of the first patient in the study (September 3, 2014). Summaries of the major changes included in each amendment are provided.

Protocol amendment 1: May 16, 2014. The following amendments were made to the protocol. The LTE was removed to shorten the total duration of treatment to 16 weeks to be consistent with the available toxicology data at that time, with the potential to add an LTE after completion of a then ongoing longer-term toxicology study. The duration of double-blind dosing was extended from 12 weeks to 16 weeks, with the longer duration of double-blind treatment expected to have a greater impact on eosinophil count and increased clinical benefit. The time point for efficacy end points was changed from week 12 to week 16 to be consistent with the increased duration of double-blind treatment. A week 2 visit was added to assess ADA and pharmacokinetic data to provide an earlier time point for these assessments. The lower limit of the eligible age range was increased from 12 years to 18 years to address concerns about adolescents potentially receiving placebo and being exposed to more than mini- mal risk. The lower weight limit was increased to 40 kg in alignment with removal of adolescents from the trial. An exclusion criterion was added for subjects requiring esophageal dilation for symptom relief within 4 weeks before baseline assessment of dysphagia or anticipated to be performed during the trial; this change was made because use of esophageal dilation could ameliorate strictures in symptomatic subjects and therefore would confound efficacy assessment in this trial. The number of biomarkers to be assessed was reduced. The restriction for concurrent medication to treat asthma or allergies during the trial was modified to enable the investigator to contact the Medical Monitor to discuss treatment options if changes to treatments were required, providing more